Phospholipid bilayers catalytically promote protein refolding, inhibit and reverse protein aggregate formation, and methods of treating neurodegenerative diseases using the same

Abstract

Here, the present inventors describe novel methods and compositions to reduce protein misfolding, the formation of protein aggregates, as well as the degradation of previously formed protein aggregates, for example by separating fibrils back into protofilaments. Additional aspects of the invention include therapeutic uses of lipid bilayers to rescue misfolded proteins in Alzheimer's and other protein misfolding diseases.

1 . A composition to promote protein re-folding comprising a lipid bilayer composed of zwitterionic and/or anionic phospholipids, wherein said lipid bilayer catalytically promotes protein re-folding associated with a disease or disorder. 
     
     
         2 . The composition of  claim 1 , wherein said zwitterionic phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). 
     
     
         3 . The composition of  claim 1 , wherein said anionic phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DOPG). 
     
     
         4 . The composition of  claim 1 , wherein said lipid bilayer comprises unilamellar vesicle having a lipid bilayer. 
     
     
         5 . The composition of  claim 1 , wherein said lipid bilayer comprises a lipid bilayer disposed on a nanoparticle configured to secure said lipid bilayer. 
     
     
         6 . The composition of  claim 1 , wherein said lipid bilayer comprises a heterogeneous lipid bilayer of DOPG and DOPC. 
     
     
         7 . The composition of  claim 6 , wherein said heterogeneous lipid bilayer of DOPG and DOPC comprises a heterogeneous lipid bilayer selected from the group consisting of:
 a heterogenous lipid bilayer having 99% DOPG and 1% DOPC;   a heterogenous lipid bilayer having 75% DOPG and 25% DOPC;   a heterogenous lipid bilayer having 50% DOPG and 50% DOPC;   a heterogenous lipid bilayer having 25% DOPG and 75% DOPC;   a heterogenous lipid bilayer having 1% DOPG and 99% DOPC; and   a heterogenous lipid bilayer having between 99-1% DOPG and between 1-99% DOPC.   
     
     
         8 . The composition of  claims 1 - 5 , wherein said lipid bilayer comprises a homogenous lipid bilayer of either DOPG or DOPC. 
     
     
         9 . The composition of  claims 1 - 8 , wherein said protein associated with a disease or disorder comprises amyloid-β (Aβ). 
     
     
         10 - 15 . (canceled) 
     
     
         16 . A composition for inhibiting the formation of protein aggregates or reversing pre-formed protein aggregates comprising a lipid bilayer composed of zwitterionic and/or anionic phospholipids, wherein said lipid bilayer catalytically inhibits or reverses the formation of said protein aggregates associated with a disease or disorder. 
     
     
         17 . The composition of  claim 16 , wherein said zwitterionic phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). 
     
     
         18 . The composition of  claim 16 , wherein said anionic phospholipid comprises 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DOPG). 
     
     
         19 . The composition of  claim 16 , wherein said lipid bilayer comprises unilamellar vesicle having a lipid bilayer. 
     
     
         20 . The composition of  claim 16 , wherein said lipid bilayer comprises a lipid bilayer disposed on a nanoparticle configured to secure said lipid bilayer. 
     
     
         21 . The composition of  claim 16 , wherein said lipid bilayer comprises a heterogeneous lipid bilayer of DOPG and DOPC. 
     
     
         22 . The composition of  claim 21 , wherein said heterogeneous lipid bilayer of DOPG and DOPC comprises a heterogeneous lipid bilayer selected from the group consisting of:
 a heterogenous lipid bilayer having 99% DOPG and 1% DOPC;   a heterogenous lipid bilayer having 75% DOPG and 25% DOPC;   a heterogenous lipid bilayer having 50% DOPG and 50% DOPC;   a heterogenous lipid bilayer having 25% DOPG and 75% DOPC;   a heterogenous lipid bilayer having 1% DOPG and 99% DOPC; and   a heterogenous lipid bilayer having between 99-1% DOPG and between 1-99% DOPC.   
     
     
         23 . The composition of  claim 16 , lipid bilayer comprises a homogenous lipid bilayer of either DOPG or DOPC. 
     
     
         24 . The composition of  claim 16 , wherein the protein aggregates comprises amyloid-β (Aβ) fibrils. 
     
     
         25 . (canceled) 
     
     
         26 . The composition of  claim 24 , wherein the β-sheet structure of said Aβ fibril is decreased. 
     
     
         27 - 55 . (canceled) 
     
     
         56 . A composition comprising a heterogeneous lipid bilayer composed of (DOPC) and (DOPG) wherein said lipid bilayer catalytically:
 promotes protein re-folding of tau, α-synuclein, and/or tumor suppressor protein p53; or   reverses the formation of said protein aggregates of tau, α-synuclein, and/or tumor suppressor protein p53; or   inhibits the formation of said protein aggregates of tau, α-synuclein, and/or tumor suppressor protein p53.   
     
     
         57 - 166 . (canceled)